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APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I

APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I. Edward A. Sausville, M.D., Ph.D. Developmental Therapeutics Program National Cancer Institute October 17, 2002. GOALS OF PRECLINICAL DRUG STUDIES. Regulatory framework.

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APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I

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  1. APPLYING PRE-CLINICAL DATA TO CLINICAL STUDIES-I Edward A. Sausville, M.D., Ph.D. Developmental Therapeutics Program National Cancer Institute October 17, 2002

  2. GOALS OF PRECLINICAL DRUG STUDIES Regulatory framework • IND = “Investigational New Drug” application = approval by FDA to conduct human studies; main criterion : SAFETY AND LIKELY REVERSIBLE TOXICITY = allows start of Phase I trials • Pediatric Phase I Oncology Drugs: Special Issues • *Few (thankfully) patients; many agents • *Unmet medical need; ethical concerns • *Prior Rx ; Concomitant meds • *Unique pediatric biology (tumor and host) vs. • value of adult data in study design

  3. PEDIATRIC PHASE I STUDIES: “CLASSICAL” NCI RECOMMENDATIONS • Begin in pediatric patients with solid tumors and • leukemias at 80% of max tol dose (MTD) in adults with solid tumors • Solid tumor and leukemia pts at each level • Escalate in 20% increments; distinguish myelosuppressive tox (desired in leukemia) vs non myeloid tox • In absence of non-myelo tox, escalate beyond • solid tumor MTD in leukemia patients. Marsoni et al. Cancer Treatment Reports 69, 1263, 1985

  4. PEDIATRIC PHASE I STUDIES: BASIS FOR RECONSIDERATION OF CLASSICAL PRACTICE • BIOLOGY: Pediatric tumors may have targets intrinsically different from adults; therefore adult data will never be available for drugs directd to those targets. • PHARMACOLOGY: Past practice weighted toward “cytotoxics” ; ? Relevance to “targeted” agents. • TIMING: Many new agents; delay in completing adult studies before application in peds neoplasms therefore exacerbate unmet need.

  5. COMPONENTS OF AN IND The goal of the pre-clinical process • “Form 1571” • Table of Contents • Intro Statement / Plan • Investigator Brochure • Clinical Protocol • Chemistry, Manufacture, Control • Pharmacology/ Toxicology • Prior Human Experience • Additional Info - Data monitoring, Quality Assurance

  6. HOW ARE PHASE I DOSE AND SCHEDULE FIXED IN ADULTS ? • Animal (usually mouse) model studies define likely active • schedules in animals bearing human-derived tumors • *Likelihood of human activity stochastic: more models • with activity, greater likelihood of human activity • *Limitations: difference between animal / human metabolism • *Drug concentrations OR effect on target provide • important ancillary info. • Toxicology according to NCI guidelines / FDA requirements • Starting dose a fraction of dose causing no or minimal • reversible toxic effect; escalate dose in steps likely to capture • reversible toxic effect

  7. PROBLEMS WITH “MTD” DRIVEN ENDPOINTS • Drugs regulating pathways important in oncogenesis are effective by combining with high affinity binding sites; therefore must distinguish “targeted” vs “non-targeted” toxicity related to these binding sites • Whether dosing beyond effect on desired target “buys” therapeutic value not clear • Therefore must define in pre-clinical studies “BIOLOGICALLY EFFECTIVE DOSE” and “MAXIMUM TOLERATED DOSE” • Use BIOLOGIC rather than TOXIC endpoints in PhaseI?

  8. REGULATORY CONSIDERATIONS FOR PRE-CLINICAL DEVELOPMENT OF ANTICANCER DRUGS [DeGeorge, et al, CCP (1998) 41: 173-185] “… The types of preclinical studies expected for support of clinical trials and marketing of a new drug depends on both the intended use of the drug and the population of patients being studied and treated. In situations where potential benefits are greatest (Advanced, life-threatening disease), greater risks of treatment toxicity can be accepted and the required preclinical testing can be minimal. …”

  9. FDA PRECLINICAL PHARMACOLOGY & TOXICOLOGY REQUIREMENTS • DRUGS • Two Species - Rodent & Non-rodent • Clinical Route & Schedule • Follow NCI Guidelines • Pharmacokinetics - Optional • BIOLOGICALS • Most Relevant Species • Clinical Route & Schedule

  10. OBJECTIVES OF PRECLINICAL TOXICOLOGY STUDIES FOR ANTI-NEOPLASTIC DRUGS • DETERMINE IN APPROPRIATE ANIMAL MODELS: • The Maximum Tolerated Dose (MTD) • Dose Limiting Toxicities ( DLT ) • Schedule-Dependent Toxicity • Reversibility of Adverse Effects • A Safe Clinical Starting Dose

  11. MouseLethality Studies DogToxicity Studies Rodent (Rat) Toxicity Studies Determine LD10 on Dx1 & Dx5 Schedules Assess safety of 1/10 LD10; Determine DLTs on Dx1 & Dx5 Schedules. Assess safety of 1/10 LD10; Determine DLTs on Dx1 & Dx5 Schedules. NCI STANDARDIZED PRECLINICAL TOXICOLOGY PROTOCOLS FOR ANTI-NEOPLASTIC AGENTS (1980 - 1988)

  12. CURRENT NCI TOX PHILOSOPHY • Agent-Directed Studies • Pharmacologically- Guided • Integrate With Preclinical Efficacy Data & the Proposed Clinical Protocol • Rational Evaluation of Role of Schedule Dependence, Pharmacokinetics & Metabolism in the Development of Toxicity • Relate Plasma Drug LeveLs and/or AUC to Safety and to Occurrence & Severity of Toxicity • Extrapolate Toxic Effects Across Species

  13. AGENT-DIRECTEDversusSTANDARD PROTOCOL DRUG DEVELOPMENT • Greater Scientific Basis for Development • Permits Greater Flexibility • Data Rich IND Submission to Support Phase I • Preclinical Potential … Less Expensive • Permits PK-Guided Dose Escalation in Phase I • Clinical Trial Potential … Shorter, Less Expensive • Optimal Schedule … Greater Chance of Success? • Patients … Greater Chance of Effective Therapy?

  14. Schedule q4Dx3, po RAT DOG MTD (Total Dose) 360 mg/m2 > 150 < 240 mg/m2 DLT Bone Marrow GI Tract Bone Marrow, GI Tract BENZOYLPHENYLUREA PRECLINICAL MTD & DLTs Starting Dose: 24 mg/m2

  15. ADDITIONAL AGENT-DIRECTED TOXICOLOGY STUDY REQUIREMENTS • Attain Efficacious Drug Levels in Plasma In Vivo • Correlate Drug Plasma Levels and/or AUC with Toxicity and Safety Across Species • Ameliorate Toxicity by Change in Route/Schedule • Compare Toxicity with Accepted Clinical Agents as Necessary

  16. SCHEDULE and ROUTE versus TOXICITY • Pyrazoloacridine: Bolus iv Neurotoxicity 1 Hr civ Bone Marrow • Penclomedine: Bolus iv Neurotoxicity 1 Hr Dx5 BM (& Neuro) 5 Hr civ Neuro & Death Oral BM • O6 –Benzylguanine: Bolus CNS, HR  Infusion Neutrophilia

  17. HOW PREDICTIVE OF HUMAN EXPERIENCE ARE THESE SAFETY-TESTING ALGORITHMS? • Predictive power varies with endpoint desired: • - 97% safe starting dose if 2-3 species (rodent plus dog) • - 83% mouse only • (Smith, A.C. Proc AACR 35: 459) • BUT: Human MTD accurately predicted by: • -mouse in 36% • -rat in 19% • -dog in 44% • NO in vitro or silico methodology has yet emerged to • predict human toxicity or dosing scheme (?marrow) NCI data

  18. CONCLUSIONS FROMILSI HUMAN TOXICITY PROJECT DATA • 71% (151/214) human toxicities(HTs) associated with • toxicities in animals • - 63% in non-rodents • - 36% in rodent plus non-rodent combinations • - 43% in rodents • 29% of human toxicities not predicted for by animals • (8HTs insufficient animal data) • Two species best predictor; • for single species non-rodent (dog and/or primate) • better than rodent (mainly rat) SOT.BiomarkersSymposium; Regul. Toxicol. 32: 56, 2000

  19. CONSIDERATIONS IN APPLYING DATA TO PEDS POPULATIONS • How closely do adult / peds MTDs correspond? • *cytotoxics? • *noncytotoxics • Are “classical” MTDs still relevant? • “Age” / maturity / nature of tox species relevant • if adult human phase I data not to drive peds dosing? • Importance of efficacy model PK / PD? • Chronicity / reversibility / age-relatedness of • target related tox’s (e.g.s): • *bone growth and anti-VEGFRs? • *skin (anti-EGFR)

  20. ACKNOWLEDGEMENTS J. Covey M. Hollingshead A. Smith J. Tomaszewski S. Decker

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